Human Immunodeficiency Virus-1 (HIV-1) infection has been reported throughout the world in both developed and developing countries. HIV-2 infection is found predominately in West Africa, Portugal, and Brazil. At the end of 2008, an estimated 1,178,350 persons aged 13 and older were living with HIV infection in the United States. Of those, 20% had undiagnosed HIV infections (CDC, “HIV Surveillance—United States, 1981-2008,” MMWR 60(21); 689-693 (2008)).
The HIV viruses are members of the Retroviridae family and, more particularly, are classified within the Lentivirinae subfamily. Like nearly all other viruses, the replication cycles of members of the Retroviridae family, commonly known as the retroviruses, include attachment to specific cell receptors, entry into cells, synthesis of proteins and nucleic acids, assembly of progeny virus particles (virions), and release of progeny viruses from the cells. A unique aspect of retrovirus replication is the conversion of the single-stranded RNA genome into a double-stranded DNA molecule that must integrate into the genome of the host cell prior to the synthesis of viral proteins and nucleic acids.
HIV encodes a number of genes including three structural genes—gag, pol, and env—that are common to all retroviruses. The envelope protein of HIV-1 is a glycoprotein of about 160 kd (gp160). During virus infection of the host cell, gp160 is cleaved by host cell proteases to form gp120 and the integral membrane protein, gp41. The gp41 portion is anchored in the membrane bilayer of the virion, while the gp120 segment protrudes into the surrounding environment. The membrane bilayer of the virion is derived from human host cells and therefore is immunologically silent, so gp120 is the major target for host antibodies on the virion. gp120 and gp41 are non-covalently associated, and free gp120 can be released from the surface of virions and infected cells. The gp120 polypeptide is also instrumental in mediating entry into the host cell.
Historically, viral vaccines have been enormously successful in the βprevention of infection by a particular virus. Therefore, when HIV was first isolated, there was a great amount of optimism that an HIV vaccine would be developed quickly. However, this optimism quickly faded, because a number of unforeseen problems emerged, and to date an efficacious HIV vaccine has not been produced as a marketable product anywhere in the world.
It is widely thought that a successful vaccine should be able to induce a strong antibody response against diverse HIV-1 strains. Antibodies, by attaching to the incoming virions, can reduce or even prevent their infectivity for target cells and possibly prevent the cell-to-cell spread of virus in tissue. There have only been three HIV vaccine randomized placebo controlled clinical trials to date, and the first two (VaxGen and STEPS) failed to protect against HIV acquisition. The failure of the Vaxgen HIV vaccine trial demonstrated that whole gp120 protein molecules alone could not serve as vaccine immunogens that protect against HIV acquisition. The failure of the STEPS HIV vaccine demonstrated that cellular immunity stimulating vaccines utilizing non-gp120-encoding determinants are not protective. The success of the third trials, RV144, showed that certain, but not all, antibodies targeted at the V1/V2 domain of gp120 could protect against HIV acquisition. Thus, there remains a need for synthetic immunogens that mimic epitopes in the V1V2 domain that can elicit an immunological response in a subject against multiple HIV strains and subtypes that exhibits features of the antibodies in the RV144 trial that protected from HIV infection, for example when administered as a vaccine.
A prior filing (U.S. patent application Ser. No. 13/612,300 to Cardozo) teaches a series of peptide immunogens derived from the V2 loop of gp120 that react specifically with serum immunoglobulins from the human subjects vaccinated in the RV144 trial. However, it is not known whether these peptides contain the epitopes targeted by the specific antibodies that protected against HIV infection as most or all subjects had serum immunoglobulins reacting with these peptides, but only very few were protected from HIV infection. One feature of the protective antibodies is that they cross-react with V1V2 domains from several HIV subtypes, including subtypes AE and B. Antibodies elicited in any mammal by vaccination with any known molecule have never been shown to cross react between the V1V2 domains of several HIV subtypes, therefore antibodies with this same property as the protective antibodies detected in humans in the RV144 trial have never been elicited in mammals prior to the present invention. As the diversity of specificities of antibodies produced by the human immune system is virtually infinite, it would not have been apparent to a skilled scientist how to elicit, by vaccination in any mammal, antibodies that cross-react with V1V2 domains from several HIV subtypes, including subtypes AE and B.
The present invention is directed to overcoming deficiencies of prior approaches to addressing HIV infection.